PROJECT SUMMARY/ABSTRACT Candidate: The applicant is a physician scientist who is an assistant professor in the Hematology Division at the University of Colorado Anschutz Medical Center. In the MD/PhD program at Oregon Health and Science University, he performed benchtop translational research under the mentorship of Brian Druker, focused on chronic myeloid leukemia. The applicant?s thesis investigated drug resistance mutations that develop in patients treated with the kinase inhibitor imatinib. In fellowship at UCSF, he focused on the development of a novel CD46- targeted antibody-drug conjugate (ADC) for multiple myeloma in the laboratory of Bin Liu. Environment: At the University of Colorado, the applicant has joined with a mentoring team with cancer stem cell expertise in primary mentor Craig Jordan and co-mentor Clay Smith. The applicant will continue close collaboration with postdoctoral mentor Bin Liu and has established a new collaboration with myeloma initiating cell expert William Matsui at Johns Hopkins. The Director of the myeloma clinical program at the University of Colorado, Dr. Tomer Mark, is another project co-mentor and will help train the applicant to design clinical trial protocols based on his laboratory findings. The applicant?s training plan during the period of this award includes bioinformatics, immunology, biostatistics and responsible conduct of research coursework, as well as programs in translational research, grant writing and clinical trial protocol development. Research: Multiple myeloma (MM) is incurable with current treatments. This implies that ?MM-initiating cells? (MM-IC) survive and have ability to regenerate the disease. It is controversial whether MM-IC have an immature phenotype or are rather genetically distinct subclones. Regardless, our current inability to eliminate MM-IC leads to relapse and eventually death in all patients. When MM becomes resistant to protease inhibitors and immunomodulatory drugs (aka ?double-refractory?), the prognosis is poor. Thus, currently there is a need for (1) curative therapy for MM and (2) effective treatments for double-refractory disease. The applicant?s long-term goal is to address this need by developing new MM-IC targeted therapies. This proposal will test an ADC that targets the cell surface complement inhibitor CD46. In theory, this ADC could be curative if CD46 is present on MM-IC. Provocatively, the CD46 gene is located on chromosome 1q, which is often genetically amplified in MM (1q+). This 1q+ is a high-risk feature and is present in most double-refractory patients. We found CD46 was highest in MM patient tissue samples with 1q+. The central hypothesis of this proposal is that CD46-ADC has unique potential to selectively eliminate 1q+ MM-IC. The first aim will determine if CD46-ADC can selectively eliminate 1q+ genetic subclones. The second will determine if CD46-ADC can eliminate MM-IC. If supported by data from this proposal, the results will be applied to patient care directly in clinical trials of CD46-ADC in MM.